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Hedgehog pathway inhibition in chondrosarcoma using the smoothened inhibitor IPI-926 directly inhibits sarcoma cell growth.

Publication ,  Journal Article
Campbell, VT; Nadesan, P; Ali, SA; Wang, CYY; Whetstone, H; Poon, R; Wei, Q; Keilty, J; Proctor, J; Wang, LW; Apte, SS; McGovern, K ...
Published in: Mol Cancer Ther
May 2014

Hedgehog (Hh) pathway inhibition in cancer has been evaluated in both the ligand-independent and ligand-dependent settings, where Hh signaling occurs either directly within the cancer cells or within the nonmalignant cells of the tumor microenvironment. Chondrosarcoma is a malignant tumor of cartilage in which there is ligand-dependent activation of Hh signaling. IPI-926 is a potent, orally delivered small molecule that inhibits Hh pathway signaling by binding to Smoothened (SMO). Here, the impact of Hh pathway inhibition on primary chondrosarcoma xenografts was assessed. Mice bearing primary human chondrosarcoma xenografts were treated with IPI-926. The expression levels of known Hh pathway genes, in both the tumor and stroma, and endpoint tumor volumes were measured. Gene expression profiling of tumors from IPI-926-treated mice was conducted to identify potential novel Hh target genes. Hh target genes were studied to determine their contribution to the chondrosarcoma neoplastic phenotype. IPI-926 administration results in downmodulation of the Hh pathway in primary chondrosarcoma xenografts, as demonstrated by evaluation of the Hh target genes GLI1 and PTCH1, as well as inhibition of tumor growth. Chondrosarcomas exhibited autocrine and paracrine Hh signaling, and both were affected by IPI-926. Decreased tumor growth is accompanied by histopathologic changes, including calcification and loss of tumor cells. Gene profiling studies identified genes differentially expressed in chondrosarcomas following IPI-926 treatment, one of which, ADAMTSL1, regulates chondrosarcoma cell proliferation. These studies provide further insight into the role of the Hh pathway in chondrosarcoma and provide a scientific rationale for targeting the Hh pathway in chondrosarcoma.

Duke Scholars

Published In

Mol Cancer Ther

DOI

EISSN

1538-8514

Publication Date

May 2014

Volume

13

Issue

5

Start / End Page

1259 / 1269

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Veratrum Alkaloids
  • Tumor Burden
  • Smoothened Receptor
  • Signal Transduction
  • Receptors, G-Protein-Coupled
  • Oncology & Carcinogenesis
  • Mice
  • Humans
  • Hedgehog Proteins
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Campbell, V. T., Nadesan, P., Ali, S. A., Wang, C. Y. Y., Whetstone, H., Poon, R., … Wunder, J. S. (2014). Hedgehog pathway inhibition in chondrosarcoma using the smoothened inhibitor IPI-926 directly inhibits sarcoma cell growth. Mol Cancer Ther, 13(5), 1259–1269. https://doi.org/10.1158/1535-7163.MCT-13-0731
Campbell, Veronica T., Puviindran Nadesan, S Amanda Ali, Chang Ye Yale Wang, Heather Whetstone, Raymond Poon, Qingxia Wei, et al. “Hedgehog pathway inhibition in chondrosarcoma using the smoothened inhibitor IPI-926 directly inhibits sarcoma cell growth.Mol Cancer Ther 13, no. 5 (May 2014): 1259–69. https://doi.org/10.1158/1535-7163.MCT-13-0731.
Campbell VT, Nadesan P, Ali SA, Wang CYY, Whetstone H, Poon R, et al. Hedgehog pathway inhibition in chondrosarcoma using the smoothened inhibitor IPI-926 directly inhibits sarcoma cell growth. Mol Cancer Ther. 2014 May;13(5):1259–69.
Campbell, Veronica T., et al. “Hedgehog pathway inhibition in chondrosarcoma using the smoothened inhibitor IPI-926 directly inhibits sarcoma cell growth.Mol Cancer Ther, vol. 13, no. 5, May 2014, pp. 1259–69. Pubmed, doi:10.1158/1535-7163.MCT-13-0731.
Campbell VT, Nadesan P, Ali SA, Wang CYY, Whetstone H, Poon R, Wei Q, Keilty J, Proctor J, Wang LW, Apte SS, McGovern K, Alman BA, Wunder JS. Hedgehog pathway inhibition in chondrosarcoma using the smoothened inhibitor IPI-926 directly inhibits sarcoma cell growth. Mol Cancer Ther. 2014 May;13(5):1259–1269.

Published In

Mol Cancer Ther

DOI

EISSN

1538-8514

Publication Date

May 2014

Volume

13

Issue

5

Start / End Page

1259 / 1269

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Veratrum Alkaloids
  • Tumor Burden
  • Smoothened Receptor
  • Signal Transduction
  • Receptors, G-Protein-Coupled
  • Oncology & Carcinogenesis
  • Mice
  • Humans
  • Hedgehog Proteins